Cancer Gene Discovery to Identify Targetable Targets

癌症基因发现以确定可靶向的靶点

• 批准号: 9321279
• 负责人: CARLO M CROCE
• 金额: $ 92.4万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-11 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321279
• 关键词: 13q14; Affect; Apoptosis; Award; BCL-2 Protein; BCL2 gene; Binding; Burkitt Lymphoma; Cachexia; Cells; Chromatin Structure; Chromosomes; Code; DNA Sequence Alteration; Dendritic Cells; Disease; Endosomes; Follicular Lymphoma; Gene Family; Gene Mutation; Genes; Germ-Line Mutation; Homologous Gene; Human; Human Genome; IL6 gene; Immunoglobulins; In complete remission; Journals; Knockout Mice; MLL gene; MYC gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; MicroRNAs; Mus; Mutation; Myoblasts; Oncogenes; Pathogenesis; Pathway interactions; Patients; Peer Review; Pharmaceutical Preparations; Proteins; Publishing; Research Personnel; Role; Scientist; Somatic Mutation; T-Cell Leukemia; T-Cell Receptor; T-Lymphocyte; TLR8 gene; Transgenic Mice; Tumor Suppressor Genes; Untranslated RNA; Work; cancer genetics; gene discovery; indexing; macrophage; microvesicles; novel; programs; prototype; public health relevance; receptor; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Previously, I was awarded the Outstanding Investigator award for two terms before the Program at NCI was discontinued. I have continued to be extremely productive to these days. My H index is 179 and I am one of the most cited scientists in the world. I have published more than 1000 articles in peer reviewed journals. I have also made many important discoveries in cancer genetics and have identified and characterized many cancer genes. My discoveries that changed the ways to think about cancer, I believe, are: the demonstration of the juxtaposition of the MYC oncogene to the immunoglobulin loci and its dysregulation in Burkitt lymphoma, the first demonstration of the specific gene alterations in human cancer. The discovery of the BCL2 gene and its involvement in follicular lymphoma and in other malignancies. The Bcl2 protein is now targeted by ABT199, a drug of Abbott that causes complete remission in patients with CLL. BCL2 is the prototype of a large family of genes that control programmed cell death, or apoptosis. The discovery of ALL1, now renamed MLL1, a gene involved in more than 50 different translocations in ALL and AML. Its dysregulation in cancer affects chromatin structure. I also discovered the partial duplication of ALL1 (MLL1) in AML. I also discovered TCL1, which is responsible for 98% of human pre T cell leukemias, and that this gene is dysregulated in most of the aggressive CLLs. I have also discovered the role of translocations involving the T cell receptor in T cell malignancies. I also generated transgenic and KO mice to validate the oncogenes and tumor suppressor genes we discovered. It was thought that all cancer genes were encoding protein products. The dogma was that only protein coding genes that represent only 2% of the human genome were important and the remaining 98% was "junk". This view was shattered by my discovery in 2002 that CLL is caused by the loss of two microRNA genes on chromosome 13q14, miR-15a and miR-16-1. Thus genes encoding non coding RNAs can also be involved in cancer pathogenesis. We also found that these two microRNAs target BCL2, the gene I discovered in 1984. We also discovered germline and somatic mutations in microRNA genes in human malignancies and that microRNAs are dysregulated in all cancers, primarily because several of them are downstream targets of pathways responsible for oncogenesis. More recently, we discovered that tumors such as lung cancer and pancreatic cancer secrete microvesicles that fuse with macrophages and dendritic cells. MiR-21 that is contained in such microvesicles is internalized, reaches the endosomes of the recipient cells and binds and activates Toll Like Receptor 8 in humans and 7 (it's homologue) in the mouse, activating the receptor. Then NF-κB is activated and IL6 and TNFalpha are secreted, facilitating tumor spreading and metastatic disease. This year we showed that fusion of microvesicles with myoblasts causes cachexia.

 描述(由申请人提供)：在NCI的项目终止之前，我曾被授予两届杰出调查员奖。直到这些天，我仍然非常富有成效。我的H指数是179，我是世界上被引用最多的科学家之一。我已经在同行评议的期刊上发表了1000多篇文章。我还在癌症遗传学方面取得了许多重要发现，并识别和表征了许多癌症基因。我相信，我的发现改变了人们对癌症的看法：在Burkitt淋巴瘤中，MYC癌基因与免疫球蛋白基因的并列及其失调的证明，首次证明了人类癌症中特定的基因变化。Bcl2基因的发现及其在滤泡性淋巴瘤和其他恶性肿瘤中的作用。Bcl2蛋白现在是ABT199的靶点，ABT199是雅培公司的一种药物，可以使CLL患者完全缓解。Bcl2是控制细胞程序性死亡或凋亡的基因大家族的原型。ALL1的发现，现在被重新命名为MLL1，一个基因参与了ALL和AML中50多种不同的易位。它在癌症中的失调会影响染色质的结构。我还发现了ALL1(MLL1)在AML中的部分复制。我还发现了TCL1，它与98%的人类前T细胞白血病有关，并且该基因在大多数侵袭性CLL中调节失调。我还发现了T细胞受体易位在T细胞恶性肿瘤中的作用。我还培育了转基因和KO小鼠，以验证我们发现的癌基因和肿瘤抑制基因。人们认为所有的癌症基因都在编码蛋白质产物。当时的信条是，只有只占人类基因组2%的蛋白质编码基因是重要的，剩下的98%是“垃圾”。2002年，我发现CLL是由染色体13q14上的两个microRNA基因miR-15a和miR-16-1丢失引起的，这一发现打破了这一观点。因此，编码非编码RNA的基因也可能参与癌症的发病机制。我们还发现，这两个microRNAs针对的是我在1984年发现的基因bcl2。我们还在人类恶性肿瘤中发现了microRNA基因的种系和体细胞突变，并且microRNAs在所有癌症中都是失调的，主要是因为其中几个是肿瘤发生途径的下游靶标。最近，我们发现肺癌和胰腺癌等肿瘤会分泌与巨噬细胞和树突状细胞融合的微泡。这种微囊中包含的MIR-21被内化，到达受体细胞的内体，结合并激活人类的Toll样受体8和小鼠的Toll样受体7(它的同系物)，激活受体。然后激活核因子-κB，分泌IL-6和肿瘤坏死因子α，促进肿瘤扩散和转移。今年，我们展示了微泡与成肌细胞的融合会导致恶病质。